Evidence of the "hit and run" characteristics of Cerebroprotein Hydrolysate-I in the treatment of neonatal HIE based on pharmacokinetic and pharmacological studies

Hypoxic ischemic encephalopathy (HIE) is the leading cause of neonatal mortality and disability, but its treatment options are very limited and there is an urgent need to further improve treatment outcomes. The present study aims to reveal the therapeutic effects, action pattern, and potential mechanisms of Cerebroprotein hydrolysate-I (CH-I), a mixture of hydrolyzed Peptides and Amino acids, for the management of HIE. To simulate the complex pathogenesis of HIE more accurately, we innovatively constructed a "triple hit" neonatal HIE rat model. The efficacy of CH-1 was examined in this model, and it was found that CH-I treatment not only significantly improved the behavior and small molecule metabolism disorders of neonatal HIE rats, but also reduced intracerebral neuronal Apoptosis, neuroinflammation, and oxidative stress levels. In addition, the neuroprotective effect of CH-I was also confirmed in the hypoxic oligodendrocyte precursor cell model. We innovatively found that CH-I could reverse myelin damage induced by HIE modeling via activating the Wnt/β-catenin signaling pathway. More importantly, a robust quantitative analysis assay for the main Peptides in CH-I was developed based on LC-MS/MS system combining Skyline software. Then the pharmacokinetics of the main Peptides was studied based on 'relative exposure approach' combining 'mixed calibration curves' strategy. The transient exposure of Peptides in vivo indicated that CH-I should exert neuroprotective effects through the "hit and run" pattern.

Cerebroprotein hydrolysate-I; Hypoxic ischemic encephalopathy; Wnt/β-catenin signaling; “hit and run” pattern.